合成路线1

The condensation of octylamine (I) with 4-bromopyridine by heating at 180 C gives (4-octylamino)piridine (III), which is then allowed to react with 1,10-dichlorodecane by heating 120-80 C.

合成路线2

By condensation of 6-(4aminophenyl)2,3,4,5-tetrahydropyridazin-3-one (I) with 4-bromopyridine (II) in hot DMF, followed by extraction of the free base with Na2CO3 and treatment with ethanolic HCl.

合成路线3

This compound can be prepared by several different ways: 1) The reaction ot 4-(chloromethyl)pyridine (I) with NaCN in toluene - water gives 4-(cyanomethyl)pyridine (II), which is condensed with methyl acrylate (III) yielding dimethyl 4-cyano 4-(4-pyridyl)pimelate (IV). The hydrolysis and decarboxylation of (IV) atfords 4-(4-pyridyl)pimelic acid (V), which is cyclized by means of potassium tert-butoxide giving 4-(4-pyridyl)cyclohexanone (VI). The acetylation of (VI) with acetic anhydride or acetylimidazole affords 2-acetyl(4-4 pyridyl)cyclohexanone (VII), which is finally cyclized with acetylacetamide (VIII) by means of dimethylamine. 2) The cyclization of (VII) with cyanoacetamide (IX) by means of piperidine gives 4-cyano-1-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydro-3(2H)-isoquinolinone (X), which is finally treated with methyl magnesium iodide in ether. 3) The condensation of 4 bromopyridine (XI) and cyclohexanedione monoethyleneketal (XII) by means of butyllithium in THF gives 4-hydroxy-4-(4-pyridyil)cyclohexanone ethyleneketal (XIII), which is dehydrated by treatment with SOCl2 and then with NaOH to afford 4-(4-pyridyl)-3-cyclohexenone ethyleneketal (XIV). Finally, this compound is hydrolyzed with HCl and reduced with H2 over Pd/C in 0.5 N HCl yielding cyclohexanone (VII), already obtained.

合成路线4

The asymmetric 1,3-dipolar cycloaddition of the nitrile oxide resulting from 4-bromo-N-hydroxybenzenecarboximidoyl chloride (I) to allyl alcohol (II) in the presence of (R,R)-diisopropyl tartrate and diethylzinc afforded the (R)-5-(hydroxymethyl)isoxazoline (III). Treatment of 4-bromopyridine (IV) with hexamethylditin and dichlorobis(triphenylphosphine)palladium yielded 4-trimethylstannylpyridine (V). Subsequent coupling of bromophenylisoxazoline (III) with stannylpyridine (V) in the presence of tris(dibenzylideneacetone)-dipalladium and tri(2-furyl)phosphine gave rise to the pyridylphenylisoxazole (VI). After conversion of (VI) to the mesylate (VII), treatment with ammonium hydroxide in a sealed vessel provided primary amine (VIII). Finally, acetylation of (VIII) with Ac2O and pyridine furnished the title amide.

合成路线5

The N-Boc protected azaspirocarboxylic acid (I) was simultaneously deprotected and esterified with ethanolic HCl to produce ester (II). Palladium-catalyzed coupling of azaspirocycle (II) with 4-bromopyridine (III) afforded the pyridyl-azaspirocarboxylic acid (IV). This was then condensed with the known amino ester (V) using EDC and HOBt to yield amide (VI). Finally, acid hydrolysis of the ethyl ester group of (VI) furnished the title compound.

合成路线6